Oral Nitrite Trial for Hypertension and Metabolic Syndrome (ONPC)

Nitrite Modulation of Hypertension, Platelet Activation, and Endothelial and Mitochondrial Function

The objective of the study is to investigate effects of inorganic sodium nitrite on the cardiometabolic and hormonal disturbances observed in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction.

Study Overview

• Status: Withdrawn
• Conditions: Hypertension; Metabolic Syndrome
• Intervention / Treatment: Drug: 14 Nitrogen (N) Sodium Nitrite; Drug: Placebo

Detailed Description

Cardiovascular disease remains the leading cause of death in the United States and worldwide. Several studies have demonstrated that fruit and vegetable rich diets significantly reduced blood pressure and reduced the risk of ischemic stroke and cardiovascular disease in general, the exact mechanisms remain poorly understood. Preclinical and clinical research over the last decade has revealed the important vasoprotective effects of nitrates and nitrites with regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction. More recent findings suggest that inorganic nitrate and nitrite therapy may be involved in the regulation of glucose-insulin homeostasis.

For this reason, development of an oral formulation of nitrite salt represents a rational avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would ensure rapid acting effects upon absorption. Nitrite could then be oxidized to nitrate via the enterosalivary circulation pathway. In this pathway, about 25% of circulating nitrate is concentrated in the saliva and reduced to nitrite by commensal mouth bacteria with nitrate reductase enzymes. The proposal will investigate the inorganic nitrite effects (in any form) on insulin sensitivity in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction. This will be the third human trial using orally delivered nitrite (previously as aqueous solution).

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Montefiore Hospital of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-60 years
• Body mass index (BMI) ≥ 30 kg/m2
• Hypertension: defined as systolic blood pressure ≥130 and/or diastolic blood pressure ≥85 mm Hg
• Waist circumference: >102 cm in men, >88 cm in women

Exclusion Criteria:

• Positive urine pregnancy test or breastfeeding
• Concurrent use of medications affecting glucose metabolism (oral hypoglycemics, insulin, atypical antipsychotics)
• Recent addition or change in dosing of hormonal contraceptive medications (Oral Contraceptive Pill (OCP), Intra Uterine Device (IUD), DepoProvera shot)
• Current use of ≥3 anti-hypertensive agents regardless of blood pressure control or normotensive on a single or double agent
• Current use of phosphodiesterase-5 (PD) inhibitors or organic nitrates. We will not exclude for dietary sources of nitrate/nitrite.
• Not stable on treatments for the prior three months or not planning to remain on current dose of medications for blood pressure, contraception, etc.
• Known chronic psychiatric or medical conditions including diabetes, liver or kidney disease or obesity syndromes
• Thyroid Stimulating Hormone (TSH) >8 milli-International unit/mL
• Smoker
• Anemia (central lab hemoglobin < 11g/dL)
• Active periodontal disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active drug; 14 Nitrogen (N) Sodium Nitrite 40mg three times daily (TID)	Drug: 14 Nitrogen (N) Sodium Nitrite; oral formulation of sodium nitrite 40 mg three times daily for 12 weeks; Other Names: sodium nitrite
Placebo Comparator: Placebo; placebo capsules three time daily (TID)	Drug: Placebo; oral formulation of matching placebo three times daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity (i.e. insulin stimulated glucose disposal)	obtained by hyperinsulinemic euglycemic clamp	baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in systolic blood pressure	ambulatory blood pressure	baseline and 12 weeks
Change in mean arterial pressure	ambulatory blood pressure	baseline and then biweekly throughout the 12 week treatment
Change in diastolic blood pressure	ambulatory blood pressure	baseline and 12 weeks
Change in methemoglobin level	by co-oximetry	baseline and then biweekly throughout the 12 week treatment

Collaborators and Investigators

• Sponsor: Gladwin, Mark, MD
• Investigators: Principal Investigator: Kara S Hughan, MD, University of Pittsburgh; Study Director: Mark Gladwin, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2020
• Primary Completion (Actual): April 13, 2021
• Study Completion (Actual): April 13, 2021

Study Registration Dates

• First Submitted: August 5, 2015
• First Submitted That Met QC Criteria: August 5, 2015
• First Posted (Estimate): August 7, 2015

Study Record Updates

• Last Update Posted (Actual): April 19, 2021
• Last Update Submitted That Met QC Criteria: April 13, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Insulin Resistance; Hyperinsulinism; Hypertension; Syndrome; Metabolic Syndrome
• Other Study ID Numbers: PRO15050540

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No